Determination of the frequency of pharmacogenomic biomarkers for the personalized cancer treatment in the Greek population
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Date
2023
Authors
Καραναστάση, Μαρίνα Ελένη
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Abstract
Pharmacogenomics (PGx) is a field of study that investigates the influence of an individual’s genome on their reaction to drugs. The integration of personalized medicine with pharmacogenomic techniques has shown great potential in enhancing the efficacy of cancer treatment. Through the examination and interpretation of a patient’s genetic makeup, medical practitioners can offer a targeted therapeutic approach with the objective of mitigating the occurrence of adverse drug reactions (ADRs) and enhancing the overall survival rates of individuals afflicted with cancer. The DPYD gene encoded the dihydropyrimidine dehydrogenase (DPD) enzyme, which serves as the rate-limiting enzyme in the catabolism of 5-fluorouracil (5-FU) in the liver. This enzyme is responsible for the breakdown of the active components of the antimetabolite fluorouracil. The presence of genetic polymorphism in the DPYD gene has been observed to have an impact on DPD function, potentially resulting in toxicity associated with the administration of 5-FU. Pre-emptive genotyping screening for risk mutations in the DPYD gene can mitigate the occurrence of early-onset fluoropyrimidine (FP)-related toxicity, in individuals undergoing cancer treatment. According to estimates, a partial deficiency of DPYD is seen in 3-5% Caucasian, whereas a full deficiency is observed in approximately 0.1-0.3% of the same population. This study analyzed six DPYD variants (c.1896T>C, c.496A>G, DPYD*4; c.1601G>A, DPYD*5; c.1627A>G, DPYD*6; c.2194G>A, and DPYD*9A; c.85T>C) in two European cohorts including Greek healthy individuals (N=435) and Dutch oncological patients (N=1068). The primary objective was to determine the Minor Allele Frequencies (MAF) of the selected DPYD variants in the Greek cohort group. The Greek cohort sample was collected in the General University Hospital of Patras and sequenced with KASP technology. The genotyping data analysis and reporting were accomplished by FRET-Capable Fluorescence Plate Reader and KlusterCaller Software program. For the statistical analysis, the Chi-square test of Goodness of Fit and Independence , were used to determine if the study population is consistent with the Hardy Weinberg Equilibrium and if the two groups share any significant differences regarding their genetic distribution of the selected variants, respectively. The primary finding of the study was that the minor allele frequency (MAF) of the DPYD*6 variant was twice as high in the GR cohort group (11%) compared to the DU group (5%), indicating a much higher prevalence of this variant in the GR population. The DPYD*9A variation had the highest prevalence in both the GR and DU groups, accounting for 21% and 22% of cases, respectively. A statistically significant distinction was observed between the two cohort groups in terms of the prevalence of DPYD*6 (p-value=0), whereas no significant difference was found for DPYD*9A (p-value=0.81202). The data presented in this study indicates that there are distinct genetic differences in the prevalence of particular DPYD variations between the two groups. In conclusion, it is recommended that the current findings should be replicated and validated in a larger study group consisted of participants of Greek ancestry, which should also include oncological patients undergoing fluoropyrimidine-treatment. This expanded study should aim to investigate the relationship between patient’s genetic profile and the manifestation of ADRs, with particular emphasis on the pathogenic variant DPYD*6. Subsequent investigations should endeavour to bolster the substantiation surrounding the significance of PGx-guided therapy by the implementation of pre-emptive genetic testing. The integration of this individualized approach into the realm of clinical practice is considered suitable, with a specific focus on mitigating ADRs and enhancing the overall quality of life for cancer patients.
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Keywords
Dihydropyrimidine dehydrogenase, Cancer, Minor allele frequencies, Pharmacogenomics, Single nucleotide polymorphism, 5-fluorouracil